As an individual ages, denervated muscle fibers become an increasingly prominent component of the skeletal musculature, whether through the normal remodelling of motor units that occurs with aging or through traumatic events that result in the breakdown and regeneration of muscle fibers. The overall goal of this project is to understand the basis for the decline in mass and force, as well as the sharply reduced restorative capacity, in denervated muscle in both young and old animals and to identify means for preventing or reversing the effects of denervation. Specific hypotheses and experiments are proposed in four areas: 1) Understanding the biology of denervated muscle in both young and old rats; 2) testing the hypothesis that denervation is a basis for many of the regressive changes found in muscle during extreme old age; 3) identifying mechanisms underlying the maintenance and restoration of denervated muscle through electrical stimulation; 4) testing the hypothesis that both the type of nerve and type of muscle determine the success of muscle regeneration as an animal ages, particularly in extreme old age. The Project involves a consortium of laboratories specializing in morphology, physiology, molecular biology and biochemistry, and many of the experiments will be conducted on muscle supplied from group experiments through an Animal Surgery core. Specific techniques include electron and confocal microscopy, cell culture, immunocytochemistry, in vitro analysis of contractile properties of muscles, in vivo motor unit analysis, in situ hybridization, Northern and Western blotting, RNase protection assays, and transfection of cells. Muscle weakness is a major limitation on a healthy lifestyle for many older individuals. The information learned from research done on this Program Project is expected to be applied to both the prevention and treatment of muscle weakness in the elderly.